Hyperkalemic periodic paralysis (HyperPP), paramyotonia congenita (PMC), and sodium channel myotonia (SCM), are dominantly inherited myotonic disorders caused by missense mutations in the skeletal muscle sodium (Na) channel. Na channels generate the muscle action potential and influence excitability of the muscle membrane through voltage-dependent mechanisms that regulate channel availability. The proposed study will investigate the pathophysiology of these diseases by (1) analyzing electrophysiological properties of mutant Na channel expressed in a myogenic cell line and (2) evaluating the physiological consequences of over-expressed wild type or mutant Na channels upon muscle function in a transgenic mouse model. Whole-cell Na currents will be measured from MM14 muscle cells transfected with tetrodotoxin-resistant versions of wild-type or mutant Na channel cDNAs to assess muscle-specific influences upon Na channel properties. In eight transgenic mouse lines, wild type or mutant Na channel gene propagation will be verified by Southern blotting, and specificity of expression will be quantitated by an RNAse protection assay. Electromyographic screening of mice for myotonia will be performed in the absence and presence of provokation by potassium loading, exercise or cooling. Muscle force and relaxation properties of intact muscle fibers in vitro will be measured under conditions of elevated extracellular potassium. Patch clamp analysis of Na currents from sarcolemmal membrane blebs will compare native channel properties with those measured previously in heterologous cells. Histological studies will look for evidence of progressive vacuolar myopathy. These studies will test whether introduction of mutant but not wild-type Na channels in mice is sufficient to induce HyperPP through a "gain of function" mechanism. Sodium channel blockers or other drugs will be compared for effectiveness in preventing abnormal muscle excitation or ameliorating muscle cell degeneration. Kinetic models will then integrate the behavior of muscle Na, K, and Cl channels to provide quantitative predictions for understanding Na channel function and the biophysical pathology of skeletal muscle in HyperPP and related myotonic disorders. The applicant is a board-certified neurologist who has obtained experience in molecular biology and electrophysiology during three years of a postdoctoral fellowship in the laboratories of Dr. Robert H. Brown, Jr. , and Dr. Stephen C. Cannon. The proposed research will establish the critical tolls needed for the applicant to become an independent investigator focusing on an expanding family of ion channel diseases.